One of the functions of NK cells is to maintain homeostasis of the immune system by controlling the expansion of activated cells, such as T cells and APC. We have found that NK cells express a receptor (CD28H) for a ligand that is upregulated on activated myeloid cells. A CD28 homolog (CD28H) encoded by the TMIGD2 gene has been identified as a new member of the CD28 family of receptors. It is expressed in primary, resting, human NK cells, and its expression is lost during stimulation with IL-2. We have shown that CD28H functions as a co-activation receptor, in combination with other co-activation receptors, to activate NK cell cytotoxicity. A screen for phosphorylated signaling proteins suggested a signaling pathway that is unusual for a receptor at the plasma membrane of a lymphocyte. The ligand of CD28H is B7-H5, encoded by the HHLA2 gene, is expressed on activated myeloid cells. We are testing the hypothesis that CD28H has a role in the NK-dependent control of inflammation, characterized by the killing of activated APC. NK cell phenotype and function (i.e. cytokine secretion, natural cytotoxicity, antibody-dependent cellular cytotoxicity) were examined in individuals chronically exposed to malaria. NK cells in blood samples of 216 individuals living in Kalifabougou, Mali were examined by multi-parameter flow cytometry. The cohort included individuals from 2 to 20-years of age. Blood samples were collected before, during, and after malaria transmission season. We are analyzing the data to determine which NK phenotypic and functional parameters correlate with several parameters, including clinical immunity, time to first malaria episode during transmission season, and parasite load (parasitemia). A striking result was the preponderance of a subset of NK cells previously described only in the context of an active CMV infection. These cells, called adaptive NK cells, arise through epigenetic reprogramming of conventional NK cells that results in greater ADCC responses. Our analysis has shown that an increased frequency of such adaptive NK cells correlates with lower parasitemia in Mali subjects. The strong ADCC activity inherent to this NK subset suggests that the well-established role of antibodies in providing clinical immunity may be due in part to lysis of antibody-coated P.f.-infected RBCs by NK cells. Antibodies acquired naturally through repeated exposure to Plasmodium falciparum are essential in controlling blood-stage malaria. Antibodies may block invasion of uninfected red blood cells (RBC) by P.f. merozoites, or promote phagocytosis or complement-mediated lysis of infected red blood cells. An unexplored mechanism for inhibition is antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells. We sought to test the hypothesis that NK cells could perform ADCC towards P.f.-infected RBC and subsequently inhibit parasite growth. We have shown that IgG isolated from clinically immune subjects living in malaria-endemic regions activated ADCC toward infected RBC by primary human NK cells and inhibited parasite growth in an in vitro assay for ADCC-dependent inhibition. RBC lysis was highly selective for infected RBC in a mixed culture with uninfected RBC. Human antibodies specific for the major antigens PfEMP1 and RIFIN were sufficient to promote NK-mediated inhibition of parasite growth. Our results demonstrate that antibody-dependent inhibition of parasite growth is achieved by NK cells in vitro, using IgG from subjects exposed to malaria, and may represent an important component of antibody-dependent clinical immunity to P.f.-infection.